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PubMed2005

Gestational exposure to cigarette smoke imperils the long-term physical and mental health of offspring.

BACKGROUND: In this study, we sought to understand whether prenatal exposure to cigarette smoke would be associated with increased offspring hospitalization through age 22 years for various physical and mental health diagnoses. METHODS: We used multivariate logistic regression to investigate the relationship between gestational exposure to cigarette smoke and offspring hospitalization for physical and mental health conditions based on International Classification of Diseases (ICD; World Health Organization) diagnoses. RESULTS: When controlling for parental psychiatric status, maternal somatic health, socioeconomic status, parity, and maternal age, youth born to mothers who smoked six or more cigarettes per day were more likely to have experienced hospitalization for neuroses (OR, 1.97), diseases of the nervous system (i.e., neurological disorders) (OR, 1.47), respiratory infections (OR, 1.28), accidents (OR, 1.44), infections (OR, 1.54), undiagnosed symptoms (OR, 1.65), and total admissions (OR, 1.48). Female offspring prenatally exposed were more likely to have experienced hospitalization for obstetric complications (OR, 2.94). No association was found for the remaining categories analyzed: blood disorders, skin diseases, psychoses, metabolic/endocrine disease, circulatory disease, digestive disease, disease of the skeletal/muscular system, physical anomalies, neoplasms, and genital/urinary disease. CONCLUSIONS: This is the first study to investigate the impact of gestational exposure to cigarette smoke on global measures of somatic and physical health in offspring. This study adds to the literature by demonstrating that smoking during pregnancy increases offspring risk for additional health outcomes not previously recognized in the literature, and that the effect of smoking during pregnancy persists throughout the developmental period. The possibility that these findings are related to lifestyle markers or smoke exposure during childhood should also be considered.

Adult↗

PubMed2026

Genetic determinants of obesity: mechanisms, clinical implications, and targeted therapies.

PURPOSE: Obesity is a major global health crisis with rising prevalence in both pediatric and adult populations, leading to an increased risk of cardiovascular, metabolic, and other chronic complications affecting all organ systems. A clear understanding of the genetic contributors to polygenic, syndromic, and monogenic obesity is essential for early diagnosis and targeted management. METHODS: Advances in genome-wide association studies (GWAS) and sequencing technologies have greatly expanded our understanding of the genetic alterations underlying this multifaceted disease and have helped in delivering personalized treatment. RESULTS: The pathogenesis of common, polygenic obesity is related to a complex interplay between genetic susceptibility and environmental factors. Syndromic obesity, a less common form, is characterized by early-onset accompanied by additional features such as developmental delay, dysmorphic traits, and various organ system involvement. The rarest form, monogenic obesity, is characterized by severe early-onset non-syndromic obesity caused by mutations in single genes regulating appetite within the hypothalamus. These monogenic obesity cases, though infrequent, have been instrumental in elucidating key pathways involved in hunger and satiety. CONCLUSION: This review provides a comprehensive summary of the most recent findings on the genetic basis of obesity across all age groups, highlighting clinical implications and emerging therapeutic opportunities.

Humans↗

PubMed2006

Diverse responses of phenology to global changes in a grassland ecosystem.

Shifting plant phenology (i.e., timing of flowering and other developmental events) in recent decades establishes that species and ecosystems are already responding to global environmental change. Earlier flowering and an extended period of active plant growth across much of the northern hemisphere have been interpreted as responses to warming. However, several kinds of environmental change have the potential to influence the phenology of flowering and primary production. Here, we report shifts in phenology of flowering and canopy greenness (Normalized Difference Vegetation Index) in response to four experimentally simulated global changes: warming, elevated CO(2), nitrogen (N) deposition, and increased precipitation. Consistent with previous observations, warming accelerated both flowering and greening of the canopy, but phenological responses to the other global change treatments were diverse. Elevated CO(2) and N addition delayed flowering in grasses, but slightly accelerated flowering in forbs. The opposing responses of these two important functional groups decreased their phenological complementarity and potentially increased competition for limiting soil resources. At the ecosystem level, timing of canopy greenness mirrored the flowering phenology of the grasses, which dominate primary production in this system. Elevated CO(2) delayed greening, whereas N addition dampened the acceleration of greening caused by warming. Increased precipitation had no consistent impacts on phenology. This diversity of phenological changes, between plant functional groups and in response to multiple environmental changes, helps explain the diversity in large-scale observations and indicates that changing temperature is only one of several factors reshaping the seasonality of ecosystem processes.

Carbon Dioxide↗

PubMed2002

Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia.

Delayed hippocampal neurodegeneration after transient global ischemia is mediated, at least in part, through the activation of terminal caspases, particularly caspase-3, and the subsequent proteolytic degradation of critical cellular proteins. Caspase-3 may be activated by the membrane receptor-initiated caspase-8-dependent extrinsic pathway and the mitochondria-initiated caspase-9-dependent intrinsic pathway; however, the precise role of these deduced apoptosis-signaling pathways in activating caspase-3 in ischemic neurons remains elusive. The authors cloned the caspase-9 gene from the rat brain and investigated its potential role in mediating ischemic neuronal death in a rat model of transient global ischemia. Caspase-9 gene expression and protease activity were extremely low in the adult brain, whereas they were developmentally upregulated in newborn rats, especially at postnatal 12 weeks, a finding consistent with the theory of an essential role for caspase-9 in neuronal apoptosis during brain development. After 15-minute transient global ischemia, caspase-9 was overexpressed and proteolytically activated in the hippocampal CA1 neurons at 8 to 72 hours of reperfusion. The temporal profile of caspase-9 activation coincided with that of cytochrome c release and caspase-3 activation, but preceded CA1 neuronal death. Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia. Furthermore, intracerebral ventricular infusion of the relatively specific caspase-9 inhibitor N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoro-methylketone before ischemia attenuated caspase-3-like activity and significantly enhanced neuronal survival in the CA1 sector. In contrast, inhibition of caspase-8 activity had no significant effect on caspase-3 activation or neuronal survival. These results suggest that the caspase-9-dependent intrinsic pathway may be the primary mechanism responsible for the activation of caspase-3 in ischemic hippocampal neurons.

Amino Acid Sequence↗

PubMed1993

Early maturation of motor-delayed children at school age.

Children underwent motor and sensory testing during each of 3 consecutive years beginning at kindergarten entrance. Children were assigned to either a motor-normal or motor-delayed group based on results from testing during the 1st year of the study. Motor-normal subjects (n = 17) had standard scores on a global motor-sensory test that fell within one standard deviation of the mean. Motor-delayed subjects (n = 12) had a global motor-sensory test standard score indicating greater than one standard deviation of motor delay and, in addition, were delayed by a minimum of one standard deviation on four of five of the motor-sensory test subtests. At the conclusion of the 3-year study, the mean standard score of the motor-delayed group remained greater than one standard deviation below the performance of the motor-normal group as measured by the global motor-sensory test. Statistical analysis using repeated measures analysis of variance indicated that the motor-delayed group made gains but did not close the gap between themselves and the motor-normal group during the 3-year study. Group x time interaction effects showed that during the study, significant gain was made by the motor-delayed group on the motor coordination subtest of the motor-sensory test. The study supports the conclusion that motor-delayed children without early intervention fail to outgrow their motor delays by age 8 years.

Adolescent↗

PubMed1995

Validity of the Peabody Developmental Gross Motor Scale as an evaluative measure of infants receiving physical therapy.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the validity of the Peabody Developmental Gross Motor Scale (PDMS-GM) as an evaluative measure of infants receiving physical therapy. SUBJECTS AND METHODS: Infants who attended an early intervention program (N = 124) were grouped by diagnosis: cerebral palsy, Down syndrome, hydrocephalus, preterm with developmental delay, full term with developmental delay, and other. The PDMS-GM was administered to each infant three times over a 6-month period by a therapist who did not provide treatment. RESULTS: Mean scaled scores and age-equivalent scores increased for each group. Individual change was examined using the reliable change index. The results indicated that the change in total raw score for 62% of the infants was greater than what could be attributed to measurement error. When minimal clinically important change was defined as 10 scaled score points, the index of responsiveness was equal to 0.5. This finding indicates that a sample size of 68 subjects per group would be needed when the PDMS-GM is used as an outcome measure in research. CONCLUSION AND DISCUSSION: The mean change scores for each group support the use of the PDMS-GM as an evaluative measure. For many infants, particularly infants with cerebral palsy, the PDMS-GM was not responsive to change over a 6-month period. The index of responsiveness suggests that the PDMS-GM should be used only as an outcome measure in large clinical trials. The PDMS-GM is not recommended for evaluating the direct effects of physical therapy but is recommended for providing a global measure of change in motor development as part of a multidimensional assessment.

Cerebral Palsy↗

PubMed2003

Global mutational analysis of NtrC-like activators in Myxococcus xanthus: identifying activator mutants defective for motility and fruiting body development.

The multicellular developmental cycle of Myxococcus xanthus requires large-scale changes in gene transcription, and recent findings indicate that NtrC-like activators play a prominent role in regulating these changes. In this study, we made insertions in 28 uncharacterized ntrC-like activator (nla) genes and found that eight of these insertions cause developmental defects. Hence, these results are consistent with the idea that M. xanthus uses a series of different NtrC-like activators during fruiting body development. Four of the eight developmental mutants we identified have motility defects. The nla1, nla19, and nla23 mutants show S-motility defects, while the nla24 mutant shows defects in both S-motility and A-motility. During development, aggregation of the nla1, nla19, and nla23 mutants is delayed slightly and the nla24 mutant shows no signs of aggregation or sporulation. The nla4, nla6, nla18, and nla28 mutants have no appreciable loss in motility, but they fail to aggregate and to sporulate normally. The nla18 mutant belongs to a special class of developmental mutants whose defects can be rescued when they are codeveloped with wild-type cells, suggesting that nla18 fails to produce a cell-cell signal required for development. The three remaining activator mutants, nla4, nla6, and nla28, appear to have complex developmental phenotypes that include deficiencies in cell-cell developmental signals.

Bacterial Proteins↗

PubMed2006

Targeting cellular memory to reprogram the epigenome, restore potential, and improve somatic cell nuclear transfer.

Successful cloning by somatic cell nuclear transfer (SCNT) is thought to require reprogramming of a somatic nucleus to a state of restored totipotentiality [Dean, W., Santos, F., Reik, W., 2003. Epigenetic programming in early mammalian development and following somatic cell nuclear transfer. Semin. Cell. Dev. Biol. 14, 93-100; Jouneau, A., Renard, J.P., 2003. Reprogramming in nuclear transfer. Curr. Opin. Genet. Dev. 13, 486-491; ]. Though SCNT-induced reprogramming is reminiscent of the reprogramming that occurs after fertilization, reprogramming a differentiated nucleus to an embryonic state is delayed and incomplete in comparison (for review, see ). This is likely due to the existence of an epigenetic-based cellular memory, or program, that serves to regulate global patterns of gene expression, and is the basis of a genome defense mechanism that silences viruses and transposons. The mechanisms of this memory include CpG methylation and modification of histones. Recent evidence by Feng et al. [Feng, Y.-Q., Desprat, R., Fu, H., Olivier, E., Lin, C.M., Lobell, A., Gowda, S.N., Aladjem, M.I., Bouhasira, E.E., 2006. DNA methylation supports intrinsic epigenetic memory in mammalian cells. PLOS Genet. 2, 0461-0470], using a transgenic experimental system, indicates that these marks may be acquired in more than one order and thus, silent heterochromatic structure can be initiated by either methylation of CpG dinucleotides or by histone modifications. In this system, however, CpG methylation appears to differ from histone modifications because it bestows a persistent epigenetic, or cellular, memory. In other words, CpG methylation can independently confer cellular memory, whereas histone modifications appear to be limited in this capacity. Therefore, in the context of genomic reprogramming induced by SCNT, efficient demethylation is likely a key (if not the only) rate-limiting step to improving the efficiency and outcomes of SCNT cloning. This review discusses the possibility of targeting cellular memory, and in particular inducing demethylation of a somatic nucleus prior to nuclear transfer, to enable reprogramming events typically carried out by oocyte factors and thereby improve developmental competence of SCNT-reconstructed embryos. Several recent published reviews of SCNT, cellular reprogramming and genomic demethylation served as valuable sources for the authors and are recommended as supplemental reading. These include the following: Bird, A., 2002. DNA methylation patterns and epigenetic memory. Gen. Dev. 16, 6-21; Grafi, G., 2004. How cells dedifferentiate: a lesson from plants. Dev. Biol. 268, 1-6; Latham, K.E., 2005. Early and delayed aspects of nuclear reprogramming during cloning. Biol. Cell 97, 119-132; Lyko, F., Brown, R., 2005. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J.Natl. Cancer Inst. 97, 1498-1506; Morgan, H.D., Santos, F., Green, K., Dean, W., Reik, W., 2005. Epigenetic reprogramming in mammals. Hum. Mol. Gen. 14, R47-R58; Szyf, M., 2005. DNA methylation and demethylation as targets for anticancer therapy. Biochemistry 70, 533-549; Buszczak, M., Spradling, A.C., 2006. Searching chromatin for stem cell identity. Cell 125, 233-236; Gurdon, J.B., 2006. From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Annu. Rev. Cell. Dev. Biol. 22, 1-22; Yoo, C.B., Jones, P.A., 2006. Epigenetic therapy of cancer: past, present and future. Nat. Rev. 5, 37-50.

Animals↗

PubMed2005

Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain.

Timely differentiation of progenitor cells is critical for development. In this study we asked whether global epigenetic mechanisms regulate timing of progenitor cell differentiation into myelin-forming oligodendrocytes in vivo. Histone deacetylation was essential during a specific temporal window of development and was dependent on the enzymatic activity of histone deacetylases, whose expression was detected in the developing corpus callosum. During the first 10 postnatal days, administration of valproic acid (VPA), the specific inhibitor for histone deacetylase activity, resulted in significant hypomyelination with delayed expression of late differentiation markers and retained expression of progenitor markers. Differentiation resumed in VPA-injected rats if a recovery period was allowed. Administration of VPA after myelination onset had no effect on myelin gene expression and was consistent with changes of nucleosomal histones from reversible deacetylation to more stable methylation and chromatin compaction. Together, these data identify global modifications of nucleosomal histones critical for timing of oligodendrocyte differentiation and myelination in the developing corpus callosum.

Acetylation↗

PubMed2005

Impaired mitotic progression and preimplantation lethality in mice lacking OMCG1, a new evolutionarily conserved nuclear protein.

While highly conserved through evolution, the cell cycle has been extensively modified to adapt to new developmental programs. Recently, analyses of mouse mutants revealed that several important cell cycle regulators are either dispensable for development or have a tissue- or cell-type-specific function, indicating that many aspects of cell cycle regulation during mammalian embryo development remain to be elucidated. Here, we report on the characterization of a new gene, Omcg1, which codes for a nuclear zinc finger protein. Embryos lacking Omcg1 die by the end of preimplantation development. In vitro cultured Omcg1-null blastocysts exhibit a dramatic reduction in the total cell number, a high mitotic index, and the presence of abnormal mitotic figures. Importantly, we found that Omcg1 disruption results in the lengthening of M phase rather than in a mitotic block. We show that the mitotic delay in Omcg1-/- embryos is associated with neither a dysfunction of the spindle checkpoint nor abnormal global histone modifications. Taken together, these results suggest that Omcg1 is an important regulator of the cell cycle in the preimplantation embryo.

Amino Acid Sequence↗

PubMed2005

A glyphosate-based pesticide impinges on transcription.

Widely spread chemicals used for human benefits may exert adverse effects on health or the environment, the identification of which are a major challenge. The early development of the sea urchin constitutes an appropriate model for the identification of undesirable cellular and molecular targets of pollutants. The widespread glyphosate-based pesticide affected sea urchin development by impeding the hatching process at millimolar range concentration of glyphosate. Glyphosate, the active herbicide ingredient of Roundup, by itself delayed hatching as judged from the comparable effect of different commercial glyphosate-based pesticides and from the effect of pure glyphosate addition to a threshold concentration of Roundup. The surfactant polyoxyethylene amine (POEA), the major component of commercial Roundup, was found to be highly toxic to the embryos when tested alone and therefore could contribute to the inhibition of hatching. Hatching, a landmark of early development, is a transcription-dependent process. Correlatively, the herbicide inhibited the global transcription, which follows fertilization at the 16-cell stage. Transcription inhibition was dose-dependent in the millimolar glyphosate range concentration. A 1257-bp fragment of the hatching enzyme transcript from Sphaerechinus granularis was cloned and sequenced; its transcription was delayed by 2 h in the pesticide-treated embryos. Because transcription is a fundamental basic biological process, the pesticide may be of health concern by inhalation near herbicide spraying at a concentration 25 times the adverse transcription concentration in the sprayed microdroplets.

Animals↗

PubMed2004

Reduced expression of the global regulator protein CsrA in Legionella pneumophila affects virulence-associated regulators and growth in Acanthamoeba castellanii.

Legionella bacteria have a developmental cycle in which they go from existing in the aquatic environment to replicating inside eukaryotic host cells. The adaptation to the new environment requires an efficient regulatory system. Overexpression of CsrA, a global regulatory protein found in a variety of gram-negative bacteria has been shown to suppress virulence-associated traits in Legionella pneumophila. Since evidence resulting only from overproduction may not be sufficient to validate the role of a regulatory protein, a csrA mutant strain, CsrA(-), with a drastically reduced production of CsrA, was created. Using RNA slot blots and Western blotting it was shown that fliA and flaA, genes which contribute to flagellation, were expressed early in the mutant. Additionally, in CsrA(-) the levels of the stationary-phase sigma factor, RpoS, and a recently described regulator of virulence traits, LetE, were increased. Growth curves of CsrA(-) bacteria were delayed with pigment production occurring at the same OD578 but at reduced levels in the mutant. Replication ability of the CsrA(-) mutant in amoebae was also affected. Based on these results, we could show that CsrA is involved in the regulation of the bacterial switch from the replicative to the transmissible form.

Acanthamoeba↗

PubMed2006

T(2)-weighted microMRI and evoked potential of the visual system measurements during the development of hypomyelinated transgenic mice.

Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.

Animals↗

PubMed2005

Adaptive changes in cardiac myosin heavy chain and creatine kinase isozymic profiles in rats native of altitude.

AIM: The developmental changes in the myosin heavy chain (MHC) profile, creatine kinase (CK) and lactate dehydrogenase (LDH) activities and isozyme expression occurring in heart were examined in rats born and living at altitude (La Paz, Bolivia, 3700 m, H(LP)) for 16 generations. We hypothesized that H(LP) rats respond differently to hypoxia than rats born and living at sea level, and secondarily exposed to altitude during 3 weeks (H(3W)). METHODS: The cardiac expression of MHC, CK and LDH was studied in left (LV) and right ventricle (RV) of H(LP) animals 1, 2, 3, 4 and 18 weeks after birth, and compared with control normoxic (C groups) and H(3W) animals. RESULTS: Rats secondarily exposed to hypoxia showed a lower alpha-MHC content than C or H(LP) rats in both LV and RV, 3 weeks after birth (P < 0.05), consistent with a delay in the maturation of the heart contractile phenotype. A global increase in the total CK activity was observed in the LV of H(3W) animals in comparison with C rats (P < 0.05), while no change was reported in H(LP) animals. In both ventricles, M-LDH activity was higher in H(3W) than in H(LP) and C rats (P < 0.05). The relative amount of alpha-MHC decreased by 20% in RV of 18-week-old H(LP) and H(3W) rats in comparison with C animals, consistent with the hypoxia-induced ventricular enlargement (P < 0.01). An increased activity of the foetal B-CK subunit was observed in both LV and RV of H(3W) rats in comparison with H(LP) and C animals (P < 0.05). CONCLUSION: This study demonstrates that rats native and living at altitude for several generations present some features relevant to genetic selection to altitude.

Adaptation, Physiological↗

PubMed1997

Infarcts in the vascular distribution of the middle cerebral artery in preterm and fullterm infants.

Twenty-three infants with an infarct in the territory of the middle cerebral artery are reported. The diagnosis was made using cranial ultrasound in all, confirmed on postmortem in two cases and on MRI, performed during the neonatal period or in infancy, in 18 of the 20 survivors. Involvement of the main branch was present in 7 cases and three of these had a gestational age of less than 35 weeks. In the other 16 infants, involvement of a cortical branch or one or more of the lenticulostriate branches was present and all but three of these had a gestational age of 34 weeks or less. While involvement of the main branch was usually diagnosed on postnatal day 1 or 2 using ultrasound, involvement of the lenticulostriate branches was noted as a wedgeshaped echogenic lesion in the caudate nucleus, thalamus or putamen, between day 4 up till day 24, and at term age in one of the cases. Neurodevelopmental outcome of those with involvement of the main branch was disappointing as all survivors developed a hemiplegia, associated with epilepsy in two; while so far only three of the other 16 infants developed cerebral palsy, one a hemiplegia and one athetoid cerebral palsy. Global delay was present in a further three cases. Infarcts in the region of the middle cerebral artery can occur in both preterm as well as fullterm infants. Involvement of the main branch also occurred in infants with a gestational age below 35 weeks and resulted in the development of a hemiplegia in all survivors. Involvement of one of the other branches was especially common in preterm infants, who had a more favourable outcome. As the lesion in the latter group was usually not present before the end of the first week, serial ultrasound up till term age is needed in order to identify these lesions.

Cerebral Arteries↗

PubMed2006

Global gene transcription patterns in in vitro-cultured fertilized embryos and diploid and haploid murine parthenotes.

To gain insights into the roles the paternal genome and chromosome number play in pre-implantation development, we cultured fertilized embryos and diploid and haploid parthenotes (DPs and HPs, respectively), and compared their development and gene expression patterns. The DPs and fertilized embryos did not differ in developmental ability but HPs development was slower and characterized by impaired compaction and blastocoel formation. Microarray analysis revealed that fertilized blastocysts expressed several genes at higher levels than DP blastocysts; these included the Y-chromosome-specific gene eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked (Eif2s3y) and the imprinting gene U2 small nuclear ribonucleoprotein auxiliary factor 1, related sequence 1 (U2af1-rs1). We also found that when DPs and HPs were both harvested at 44 and 58 h of culture, they differed in the expression of 38 and 665 genes, respectively. However, when DPs and HPs were harvested at the midpoints of 4-cell stage (44 and 49 h, respectively), no differences in expression was observed. Similarly, when the DPs and HPs were harvested when they became blastocysts (102 and 138 h, respectively), only 15 genes showed disparate expression. These results suggest that while transcripts needed for early development are delayed in HPs, it does progress sufficiently for the generation of the various developmental stages despite the lack of genetic components.

Animals↗

PubMed2005

Changing chromatin dynamics and nuclear organization during differentiation in Drosophila larval tissue.

Global changes in gene expression and exit from the cell cycle underlie differentiation. Therefore, understanding chromatin behavior in differentiating nuclei and late G1 is key to understanding this developmental event. A nuclear event that has been shown to specifically occur in late G1 is the association of two heterochromatic blocks in Drosophila. The brown(Dominant) (bw(D)) chromosome of Drosophila melanogaster contains a large block of heterochromatin near the end of 2R. This distal block associates with centric heterochromatin (2Rh), but not until at least 5 hours into G1. We used the bw(D) allele as a model for nuclear organization to determine whether its association with the heterochromatic compartment of the second chromosomes (2Rh) strictly requires differentiation or if this change is a stochastic event, its occurrence being proportional to time spent in G1/G0 phase of the cell cycle. Fluorescence in situ hybridization on eye imaginal discs showed increased association between the bw locus and 2Rh in differentiated cells. Interestingly, an increase in the number of nuclei showing bw(D)-2Rh association in the brains of developmentally delayed larvae that were compromised for differentiation was also observed. Live fluorescence imaging showed that the kinetics of chromatin movement remains unchanged in the developmentally arrested nuclei. These observations suggest that nuclear reorganization is not directly controlled by specific inductive signals during differentiation and that this nuclear reorganization can happen in a cell, regardless of differentiation state, that is arrested in the appropriate cell cycle stage. However, we did see changes that appear to be more directly correlated with differentiation. Dynamic imaging in eye imaginal discs showed that the movement of chromatin is more constrained in differentiated cells, implying that confinement of loci to a smaller nuclear space may help to maintain the changed organization and the transcription profile that accompanies differentiation.

Alleles↗

PubMed2004

Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus.

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.

Animals↗